The Kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136

Blume‐Jensen, Peter; Janknecht, Ralf; Hunter, Tony

doi:10.1016/s0960-9822(98)70302-1

Cited by 329 publications

(272 citation statements)

References 18 publications

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“…Comparisons between total cell lysates and phosphotyrosine purifications ( Figure 5) showed that KIT, PI3-K (regulatory and catalytic subunits), SHC and GRB2 were strongly tyrosine phosphorylated in a KIT-dependent manner in both GIST882 and GIST48 cell lines. These findings are consistent with KIT oncogenic activation of the RAS/RAF/MAPK and PI3-K/AKT pathways, which are regulated by activation of GRB2/SHC and PI3-K, respectively (Tauchi et al, 1994;Blume-Jensen et al, 1998). Recruitment of GRB2 and SHC adaptor proteins to RTK-derived oncogenes has been shown to be sufficient for morphological cell transformation and experimental metastases (Saucier et al, 2002), whereas Figure 6 (a-c) Cell density effects on KIT/PDGFR-dependent activation of kinase signaling proteins in GIST48, with and without KIT/PDGFR inhibition by PKC412.…”

Section: Discussionsupporting

confidence: 73%

KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance

Zhu

Fletcher

et al. 2007

Oncogene

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Most gastrointestinal stromal tumors (GISTs) express oncogenic and constitutively active forms of the KIT or platelet-derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinase proteins, and these kinase oncoproteins serve as targets for effective therapies. Given that mutant KIT oncoproteins serve crucial transforming roles in GISTs, we evaluated interactions with the KIT oncoproteins and determined signaling pathways that are dependent on KIT oncogenic activation in GISTs. Tyrosine-phosphorylated KIT oncoproteins interacted with PDGFRA, PDGFRB, phosphatidylinositol 3-kinase (PI3-K) and PKCh in GIST cells, and these interactions were abolished by KIT inhibition with imatinib or PKC412 or KIT RNAi. Notably, tyrosine-phosphorylated PDGFRA was prominent in frozen GIST tumors expressing KIT oncoproteins, suggesting that KIT-mediated PDGFRA phosphorylation is an efficient and biologically consequential mechanism in GISTs. Activated signaling intermediates were identified by immunoaffinity purification of tyrosine-phosphorylated proteins in GIST cells before and after treatment with KIT inhibitors, and these analyses show that GRB2, SHC, CBL and MAPK activation are largely KIT dependent in GISTs, whereas PI3-K, STAT1 and STAT3 activation are partially KIT dependent. In addition, we found that phosphorylation of several tyrosine kinase proteins -including JAK1 and EPHA4 -did not depend on KIT activation. Likewise, paxillin activation was independent of the KIT oncogenic signal. These studies identify signaling pathways that can provide both KIT-dependent and KIT-independent therapeutic synergies in GIST, and thereby highlight clinical strategies that might consolidate GIST therapeutic response to KIT/PDGFRA inhibition.

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Section: Discussionsupporting

confidence: 73%

KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance

Zhu

Fletcher

et al. 2007

Oncogene

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“…Several groups have since shown that Ser"$' can be specifically phosphorylated by PKB in itro and in transfected cells [115][116][117]. With the use of ion-exchange chromatography, PKB was found to be the major Ser"$' kinase in PDGF-treated fibroblasts, although other protein kinases, such as calmodulin-dependent protein kinase-II and p90RSK, can also phosphorylate Ser"$' in itro.…”

Section: How Does Pkb Protect Cells ?mentioning

confidence: 99%

Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

Coffer

Jin

Woodgett

1998

Biochemical Journal

988

818

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While a plethora of extracellular molecules exist that modulate cellular functions via binding to membrane receptors inside the cell, their actions are mediated by relatively few signalling mechanisms. One of these is activation of phosphatidylinositol 3-kinase (PI-3K), which results in the generation of a membranerestricted second messenger, polyphosphatidylinositides containing a 3h-phosphate. How these molecules transduced the effects of agonists of PI-3K was unclear until the recent discovery that several protein kinases become activated upon exposure to 3h-phosphorylated inositol lipids. These enzymes include protein kinase B (PKB)\AKT and PtdIns(3,4,5)P $ -dependent kinases 1 and 2, the first two of which interact with 3h-phosphorylated ORIGINS OF AKTThe AKR strain of mice exhibit a high incidence of leukaemias and lymphomas from spontaneous thymoma [1]. A retrovirus termed AKT8 was isolated from one of these lines derived from a spontaneous thymoma. This virus was demonstrated to uniquely transform only mink lung cells (CCL64) in culture, while virus inoculated into newborn mice was shown to be tumorigenic [2]. The non-viral DNA component transduced from the mouse genome was subsequently identified, and two human homologues, AKT1 and AKT2, cloned [3]. The location of the human AKT locus was mapped to chromosome 14q32, proximal to the immunoglobulin-heavy-chain locus [4], a region frequently affected by translocations and inversions in human Tcell leukaemia\lymphoma, mixed-lineage childhood leukaemia and clonal T-cell proliferations in ataxia telangiectasia, supporting a role for this oncogene in formation of a variety of tumours [5]. Analysis of a panel of human tumours revealed a 20-fold amplification of AKT1 in a primary gastric adenocarcinoma. AKT2, on the other hand, was mapped to chromosome region 19q13.1-q13.2 and shown to be amplified and overexpressed in several ovarian carcinoma and pancreatic cancer cell lines [6,7]. A recent large-scale study of AKT2 alterations in ovarian and breast tumours revealed amplification in 12.1 % ovarian and 2.8 % breast carcinomas [8]. Furthermore, amplification of AKT2 was especially frequent in undifferentiated tumours, suggesting that AKT2 alterations may be associated with tumour aggressiveness.Abbreviations used : PI-3K, phosphatidylinositol 3-kinase ; PKB, protein kinase B ; PKA, protein kinase A ; PKC, protein kinase C ; RAC-PK, related to A-and C-kinase ; PH, pleckstrin homology ; PtdIns, phosphoinositide ; PDGF, platelet-derived growth factor ; EGF, epidermal growth factor ; bFGF, basic fibroblast growth factor ; IL, interleukin ; ERK, extracellular-signal-regulated kinase ; Btk, Bruton tyrosine kinase ; PDK, PtdIns(3,4,5)P 3 -dependent kinase ; MAPKAP, mitogen-activated protein kinase-activated protein ; SH2, Src homology 2 ; gag, group-specific antigen ; GLUT, glucose transporter ; GSK, glycogen synthase kinase ; PFK2, 6-phosphofructose-2-kinase ; IGF, insulin-like growth factor ; 4E-BP1, 4E-binding protein ; PHAS, pH-and acid-stable ; BCR-ABL, breakpoint...

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“…PIP3 allows the recruitment of the phosphoinositide-dependant kinase 1 (PKD1), which activates the Akt/PKB protein. The proapoptotic Bcl2-family protein, Bad, and caspase 9 are inactivated by phosphorylation via Akt/ PKB [110]. The forkhead transcription factor (FKHR1), involved in the expression of proapoptotic factors Bim and FasL, is also inhibited by the action of Akt/PKB [111].…”

Section: Role Of the Pi3k Pathwaymentioning

confidence: 99%

Host cell manipulation by the human pathogen Toxoplasma gondii

Laliberté

Carruthers

2008

Cell. Mol. Life Sci.

158

123

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Toxoplasma gondii is an obligate intracellular parasite that can infect virtually any nucleated cell. During cell invasion Toxoplasma creates a subcellular compartment termed the parasitophorous vacuole, which acts as an interface between the parasite and host cytoplasm, and in many cases serves as a platform for modulation of several host cell functions that support parasite replication and infection. Spatial reorganization of host organelles and the remodeling of the cytoskeleton around the parasitophorous vacuole are observed early following entry and recent evidence suggests this interior redecorating promotes nutrient acquisition by the parasite. New findings also reveal that T. gondii manipulates signaling pathways of the host cell by deploying parasite kinases and a phosphatase, including at least two that infiltrate the host nucleus. T. gondii infection additionally controls several cellular pathways to establish an anti-apoptotic environment in a variety of cell types, and to subvert immune cells as a conduit for dissemination. In this review we discuss these recent developments in understanding how T. gondii achieves widespread success as a human and animal parasite by manipulating its host.

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The Kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136

Cited by 329 publications

References 18 publications

KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance

KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance

Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

Host cell manipulation by the human pathogen Toxoplasma gondii

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